Joining tissues with composition of bioabsorbable isocyanate and amine-substituted polyalkylene glycol

ABSTRACT

Bioabsorbable compounds which include a polyalkylene oxide backbone with two or more isocyanate substituents are useful as one component adhesives. Absorbable compositions useful as a two component adhesive contain a) a polyethylene oxide having two or more amine substituents with b) a bioabsorbable diisocyanate compound, or alternatively contain a) a polyethylene oxide having two or more isocyanate substituents with b) a bioabsorbable diamine compound, or, alternatively contain a) a bioabsorbable diisocyanate compound and b) a bioabsorbable diamine compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 11/774,875filed Jul. 9, 2007, allowed, which is a divisional of U.S. patentapplication Ser. No. 11/523,197 filed Sep. 18, 2006, now U.S. Pat. No.7,241,846, which is a divisional of U.S. application Ser. No. 10/176,280filed Jun. 19, 2002, now U.S. Pat. No. 7,129,300, which claims priorityto U.S. Provisional Patent Application Ser. No. 60/309,074 filed Jul.31, 2001, the disclosures of each of which are incorporated herein intheir entirety by this reference.

BACKGROUND

1. Technical Field

This disclosure relates to bioabsorbable compounds and compositionsuseful as surgical adhesives and sealants.

2. Description of the Related Art

In recent years there has developed increased interest in replacing oraugmenting sutures with adhesive bonds. The reasons for this increasedinterest include: (1) the potential speed with which repair might beaccomplished; (2) the ability of a bonding substance to effect completeclosure, thus preventing seepage of fluids; and (3) the possibility offorming a bond without excessive deformation of tissue.

Studies in this area, however, have revealed that, in order for surgicaladhesives to be accepted by surgeons, they must possess a number ofproperties. First, they must exhibit high initial tack and an ability tobond rapidly to living tissue. Secondly, the strength of the bond shouldbe sufficiently high to cause tissue failure before bond failure.Thirdly, the adhesive should form a bridge, preferably a permeableflexible bridge. Fourthly, the adhesive bridge and/or its metabolicproducts should not cause local histotoxic or carcinogenic effects.

A number of adhesive systems such as alkyl cyanoacrylates,polyacrylates, maleic anhydride/methyl vinyl ethers, epoxy systems,polyvinyl alcohols, formaldehyde and gluteraldehyde resins andisocyanates have been investigated as possible surgical adhesives. Nonehas gained acceptance because each fails to meet one or more of thecriteria noted above. The principal criticism of these systems has beenthe potential toxicity problems they pose.

It would be desirable to provide novel metabolically-acceptableisocyanate-based adhesives and in particular metabolically-acceptablesurgical adhesives. It would also be desirable to providemetabolically-acceptable surgical adhesives which are biodegradable. Itwould also be desirable to provide a method for closing wounds in livingtissue by use of novel, metabolically-acceptable surgical adhesiveswhich are low in toxicity as a consequence of their physical properties.

SUMMARY

A bioabsorbable compound is provided which includes a polyalkylene oxidebackbone with two or more isocyanate substituents and which is useful asa one component adhesive. In particularly useful embodiments, thepolyalkylene backbone has a branched or multi-arm structure. Forexample, in one embodiment the compound corresponds to the followingformula (I):R′_(4-n)—C—(R)_(n)  (I)wherein the R′ groups can be the same or different at each occurrenceand are each individually selected from the group consisting of —H andC₁ to C₈ alkylene groups and the R groups can be the same or differentat each occurrence and are each individually selected from the groupconsisting of polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having formula (II) setforth below, with the proviso that at least two of the R groups arepolyalkylene oxide groups substituted with at least one isocyanategroup, and n is a number of from 2 to 4.

The group of formula (II) is an isocyanate group having the followingstructure:—[A]_(n)—NCO  (II)wherein A is a bioabsorbable group and is preferably derived from anymonomer known to form a bioabsorbable polymer and n is from 1 to about20. Suitable monomers from which the bioabsorbable group can be derivedinclude glycolic acid, glycolide, lactic acid, lactide,1,4-dioxane-2-one, 1,3-dioxane-2-one, ε-caprolactone and the like.

In another embodiment wherein the polyalkylene backbone has a branchedor multi-arm structure, the compound corresponds to the followingformula (III):

wherein R is the same or different at each occurrence and are eachindividually selected from the group consisting of —H, C₁ to C₈ alkylenegroups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having formula (II) setforth above, with the proviso that at least two of the R groups arepolyalkylene oxide groups substituted with at least one isocyanategroup, and n is 2 to 6.

In another embodiment an absorbable composition useful as a twocomponent adhesive is provided by combining a) a polyethylene oxidehaving two or more amine substituents with b) a bioabsorbablediisocyanate compound. The polyethylene oxide having two or more aminesubstituents includes a polyalkylene oxide backbone that is preferablybranched or multi-armed. The bioabsorbable diisocyanate compound can beof the same structure as described above with respect to the onecomponent adhesive embodiments, or an oligomeric bioabsorbablediisocyanate compound of the following formula (IV):OCN—(A)_(p)—(CH₂)_(q)—(A)_(p)—NCO  (IV)wherein A is as defined above, and p is 1 to 20 and q is 1 to 10.

In yet another embodiment an absorbable composition useful as a twocomponent adhesive is provided by combining a) a polyethylene oxidehaving two or more isocyanate substituents with b) a bioabsorbablediamine compound. The polyethylene oxide having two or more isocyanatesubstituents includes a polyalkylene oxide backbone that is preferablybranched or multi-armed. The bioabsorbable diamine compound can be ofthe same structure as described above with respect to the previous twocomponent adhesive embodiment, or an oligomeric bioabsorbable diaminecompound of the following formula (X):NH₂—(CH₂)_(w)—(B)_(y)—(CH₂)_(w)—NH₂  (X)wherein B is a bioabsorbable group and w is 2 to 6 and y is 1 to 20.Bioabsorbable groups (B) include, for example, groups derived from anymonomer known to form a bioabsorbable polymer (including but not limitedto glycolic acid, glycolide, lactic acid, lactide, 1,4-dioxane-2-one,1,3-dioxane-2-one, ε-caprolactone and the like) or groups derived from adiacid which will provide an absorbable linkage (including but notlimited to succinic acid, adipic acid, malonic acid, glutaric acid,sebacic acid, diglycolic acid and the like).

The bioabsorbable compounds and compositions described herein are usefulas surgical adhesives and/or sealants for joining portions of bodytissue together or for joining surgically implantable devices to bodytissue.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT(S)

The bioabsorbable compounds described herein are useful as surgicaladhesives and sealants and include a polyalkylene oxide backbonesubstituted with one or more isocyanate groups. The polyalkylene oxidebackbone can be derived from any C₂-C₆ alkylene oxide and can behomopolymeric or copolymeric. Thus, for example, the polyalkylene oxidebackbone can be derived from ethylene oxide and be a polyethylene oxide(PEO) backbone. As another example, the polyalkylene oxide backbone canbe derived from propylene oxide and be a polypropylene oxide (PPO)backbone. As yet another example, a combination of ethylene oxide andpropylene oxide can be used to form a random or block copolymer as thebackbone. The molecular weight of the polyalkylene oxide backbone shouldbe selected to provide desired physical characteristics to the finalcompound. Preferred backbones have molecular weights in the range of 500to 20,000, preferably 1000 to 10,000, most preferably 2000 to 3500.

In particularly useful embodiments, the polyalkylene oxide backbone hasa branched or multi-arm structure. For example, the polyalkylene oxidebackbone can be the result of polymerizing alkylene oxide monomer in thepresence of a multifunctional (e.g., polyhydric) initiator. Reactionconditions for producing branched or multi-arm polyalkylene oxidebackbones are known to those skilled in the art.

In one embodiment the bioabsorbable compound corresponds to followingformula (I):R′_(4-n)—C—(R)_(n)  (I)wherein the R′ groups can be the same or different at each occurrenceand are each individually selected from the group consisting of —H andC₁ to C₈ alkylene groups and the R groups can be the same or differentat each occurrence and are each individually selected from the groupconsisting of polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having formula (II) setforth below, with the proviso that at least two of the R groups arepolyalkylene oxide groups substituted with at least one isocyanategroup, and n is a number of from 2 to 4.

The group of formula (II) is an isocyanate group having the followingstructure:—[A]_(n)—NCO  (II)wherein A is a bioabsorbable group and is preferably derived from anymonomer known to form a bioabsorbable polymer and n is from 1 to about20. Suitable monomers from which the bioabsorbable group can be derivedinclude glycolic acid, glycolide, lactic acid, lactide,1,4-dioxane-2-one, 1,3-dioxane-2-one, ε-caprolactone and the like.

In another embodiment, the compound corresponds to the following formula(III):

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having formula (II) setforth above, with the proviso that at least two of the R groups arepolyalkylene oxide groups substituted with at least one isocyanategroup, and n is 2 to 6.

While the isocyanate substituents are shown in formula (I) and formula(III) as being terminally located on the polyalkylene oxide arms, itshould be understood that substitution of the isocyanate groups at oneor more location along the polyalkylene oxide arms is also contemplated.Likewise, although a single isocyanate group per polyalkylene oxide armis shown, it is contemplated that more than one and up to ten or moreisocyanate groups per polyalkylene oxide arm may be present.

The number of isocyanate groups present on the polyalkylene oxidebackbone is selected to provide desired physical characteristics to thecompound upon exposure to moisture. A greater degree of substitutionwill provide greater cross-linking which will provide a material thatexhibits less swelling and less compliance. A lower degree ofsubstitution will yield a less cross-linked material having greatercompliance.

The present compounds can be prepared by reacting a polyalkylene oxidebackbone having two or more hydroxyl groups with a molar excess ofdiacid to provide a polyalkylene diacid. This will add the bioabsorbablegroup to the polyalkylene oxide backbone and provide free acid groups.Suitable diacids which will provide an absorbable linkage will beapparent to those skilled in the art and include succinic acid, adipicacid, malonic acid, glutaric acid, sebacic acid, diglycolic acid and thelike. While the exact reaction conditions will depend upon the specificstarting components, generally speaking the polyalkylene oxide backboneand the diacid are reacted at temperatures in the range of 25° C. to150° C., for a period of time from 30 minutes to 24 hours at atmosphericpressure in the presence of a transesterification catalyst such as, forexample stannous octoate, stannous chloride, diethyl zinc or zirconiumacetylacetonate.

Once a diacid is formed, conversion thereof to an isocyanate can beaccomplished by techniques within the purview of those skilled in theart. For example, the free acid groups can be reacted with thionylchloride to produce the corresponding acyl chloride followed by reactionwith sodium azide to provide isocyanate groups. This conversion isconducted utilizing a suitable solvent such as, for example, THF,chloroform or benzene.

Upon crosslinking, the present bioabsorbable compounds can be used assingle component adhesives or sealants. Cross-linking is normallyperformed by exposing the compound to water in the presence of acatalyst, such as tertiary amine catalyst.

While not wishing to be bound by any theory, it is believed that thewater reacts with the isocyanate groups of the present decarboxylates tothe corresponding amine and carbon dioxide. The amine reacts withadditional isocyanate to form polyurea which foams due to thesimultaneous evolution of carbon dioxide thereby forming a porous,polymeric bridge.

The exact reaction conditions for achieving cross-linking will varydepending on a number of factors such as the particular bioabsorbablecompound employed, the degree of isocyanate substitution, the specificisocyanate present on the polyalkylene backbone and the desired degreeof cross-linking. Normally, the cross-linking reaction is conducted attemperatures ranging from 20° C. to about 40° C. for thirty seconds toabout one hour or more. The amount of water employed will normally rangefrom about 0.05 moles to 1 moles per mole of bioabsorbable compound.While water is a preferred reactant to effect cross-linking it should beunderstood that other compounds could also be employed either togetherwith or instead of water. Such compounds include diethylene glycol,polyethylene glycol and diamines, such as, for example, diethylaminopropanediol. Suitable catalysts for use in the cross-linking reactioninclude 1,4 diazobicyclo [2.2.2]octane, triethylamine, anddiethylaminoethanol.

The amount of catalyst employed can range from about 0.005 grams toabout 5.0 grams per kilogram of compound being cross-linked.

When the bioabsorbable compound is intended for implantation it ispossible to effectuate cross-linking in situ using the water naturallypresent in a mammalian body or with added water. However, to moreprecisely control the conditions and extent of cross-linking, it may beadvantageous to partially cross-link the compound prior to its use as animplant.

The bioabsorbable compounds described herein can also be cross-linked bythe application of heat alone, or by exposure to diamine vapor. Thesecross-linking techniques are particularly useful when the compounds areto be used as a coating, rather than as an adhesive or sealant.

In another embodiment a composition useful as a tissue adhesive orsealant includes a polyalkylene oxide having one or more aminesubstituents combined with a bioabsorbable isocyanate compound.

The amine-substituted polyalkylene oxide can be derived from any C₂-C₆alkylene oxide and can be homopolymeric or copolymeric. Thus, forexample, the amine-substituted polyalkylene oxide can be derived fromethylene oxide and be an amine-substituted polyethylene oxide (PEO). Asanother example, the polyalkylene oxide can be derived from propyleneoxide and be an amine-substituted polypropylene oxide (PPO). As yetanother example, a combination of ethylene oxide and propylene oxide canbe used to form a random or block copolymer as the amine-substitutedpolyalkylene oxide. The molecular weight of the amine-substitutedpolyalkylene oxide should be selected to provide desired physicalcharacteristics to the final composition. The molecular weight of thepolyalkylene oxide backbone should be selected to provide desiredphysical characteristics to the final compound. Preferred backbones havemolecular weights in the range of 500 to 20,000, preferably 1000 to10,000, most preferably 2000 to 3500.

In particularly useful embodiments, the polyalkylene oxide backbone hasa branched or multi-arm structure. For example, the polyalkylene oxidebackbone can be the result of polymerizing alkylene oxide monomer in thepresence of a multifunctional (e.g., polyhydric) initiator. Reactionconditions for producing branched or multi-arm polyalkylene oxidebackbones are known to those skilled in the art.

In one embodiment the amine-substituted polyalkylene oxide compoundcorresponds to following formula (IV):R′_(4-n)—C—(R)_(n)  (IV)wherein the R′ groups can be the same or different at each occurrenceand are each individually selected from the group consisting of —H andC₁ to C₈ alkylene groups and the R groups can be the same or differentat each occurrence and are each individually selected from the groupconsisting of polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one amine group, with the proviso that atleast two of the R groups are polyalkylene oxide groups substituted withat least one amine group, and n is a number of from 2 to 4.

In another embodiment, the amine-substituted polyalkylene oxide compoundcorresponds to the following formula (V):

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one amine group, with the proviso that atleast two of the R groups are polyalkylene oxide groups substituted withat least one amine group, and n is 2 to 6.

The amine groups in the compounds of formula (IV) and formula (V) can beterminally located on the polyalkylene oxide arms, or, alternatively,substitution of the amine groups at one or more location along thepolyalkylene oxide arms. Likewise, although a single amine group perpolyalkylene oxide arm is preferred, it is also contemplated that morethan one and up to ten or more amine groups per polyalkylene oxide armmay be present.

The number of amine groups present on the polyalkylene oxide backbone isselected to provide desired physical characteristics to the compoundupon exposure to moisture. A greater degree of substitution will providegreater cross-linking which will provide a material that exhibits lessswelling and less compliance. A lower degree of substitution will yielda less cross-linked material having greater compliance.

The preparation of amine-substituted polyalkylene oxides is within thepurview of those skilled in the art. In fact, suitable amine-substitutedpolyalkylene oxides are commercially available from Shearwater Polymers,Inc., Huntsville, Ala. Preferably, the amine-substituted polyalkyleneoxide is a diamine.

The amine-substituted polyalkylene oxide is combined with abioabsorbable isocyanate, preferably a bioabsorbable diisocyanate.

In one particularly useful embodiment, the bioabsorbable isocyanate thatis combined with the amine-substituted polyalkylene oxide includes apolyalkylene oxide backbone substituted with one or more isocyanategroups. The polyalkylene oxide backbone can be derived from any C₂-C₆alkylene oxide and can be homopolymeric or copolymeric. Thus, forexample, the polyalkylene oxide backbone can be derived from ethyleneoxide and be a polyethylene oxide (PEO) backbone. As another example,the polyalkylene oxide backbone can be derived from propylene oxide andbe a polypropylene oxide (PPO) backbone. As yet another example, acombination of ethylene oxide and propylene oxide can be used to form arandom or block copolymer as the backbone. The molecular weight of thepolyalkylene oxide backbone should be selected to provide desiredphysical characteristics to the final compound. Preferred backbones havemolecular weights in the range of 500 to 20,000, preferably 1000 to10,000, most preferably 2000 to 3500.

In particularly useful embodiments, the polyalkylene oxide backbone hasa branched or multi-arm structure. For example, the polyalkylene oxidebackbone can be the result of polymerizing alkylene oxide monomer in thepresence of a multi-functional (e.g., polyhydric) initiator. Reactionconditions for producing branched or multi-arm polyalkylene oxidebackbones are known to those skilled in the art.

In one embodiment the bioabsorbable isocyanate compound that is combinedwith the amine-substituted polyalkylene oxide compound corresponds tofollowing formula (I):R′_(4-n)—C—(R)_(n)  (I)wherein the R′ groups can be the same or different at each occurrenceand are each individually selected from the group consisting of —H andC₁ to C₈ alkylene groups and the R groups can be the same or differentat each occurrence and are each individually selected from the groupconsisting of polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having formula (II) setforth below, with the proviso that at least two of the R groups arepolyalkylene oxide groups substituted with at least one isocyanategroup, and n is a number of from 2 to 4.

The group of formula (II) is an isocyanate group having the followingstructure:—[A]_(n)—NCO  (II)wherein A is a bioabsorbable group and is preferably derived from anymonomer known to form a bioabsorbable polymer and n is from 1 to about20. Suitable monomers from which the bioabsorbable group can be derivedinclude glycolic acid, glycolide, lactic acid, lactide,1,4-dioxane-2-one, 1,3-dioxane-2-one, ε-caprolactone and the like.

In another embodiment, the absorbable isocyanate compound that iscombined with the amine-substituted polyalkylene oxide compoundcorresponds to the following formula (III):

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having formula (II) setforth above, with the proviso that at least two of the R groups arepolyalkylene oxide groups substituted with at least one isocyanategroup, and n is 2 to 6.

While the isocyanate substituents are shown in formula (I) and formula(III) as being terminally located on the polyalkylene oxide arms, itshould be understood that substitution of the isocyanate groups at oneor more location along the polyalkylene oxide arms is also contemplated.Likewise, although a single isocyanate group per polyalkylene oxide armis shown, it is contemplated that more than one and up to ten or moreisocyanate groups per polyalkylene oxide arm may be present.

The number of isocyanate groups present on the polyalkylene oxidebackbone is selected to provide desired physical characteristics to thecompound upon exposure to moisture and/or to the multifunctional amine.A greater degree of substitution will provide greater cross-linkingwhich will provide a material that exhibits less swelling and lesscompliance. A lower degree of substitution will yield a lesscross-linked material having greater compliance.

In another embodiment, the bioabsorbable diisocyanate that is combinedwith the amine-substituted polyalkylene oxide compound has the followingmolecular structure:OCN—(A)_(p)—(CH₂)_(q)—(A)_(p)—NCO  (VI)wherein A is a bioabsorbable group and is preferably derived from anymonomer known to form a bioabsorbable polymer and p is from 1 to 20 andq is from 1 to 10. Preferably, the bioabsorbable group [A] is derivedfrom a compound selected from the group consisting of glycolic acid,glycolide, lactic acid, lactide, ε-caprolactone, p-dioxanone, andtrimethylene carbonate or substituted alkylene carbonates such asdimethyl trimethylene carbonate.

Those skilled in the art will readily envision reaction schemes forpreparing useful bioabsorbable isocyanates. For example, bioabsorbablediisocyanates can be prepared by first preparing a bioabsorbableoligomer and then endcapping with isocyanate. Methods for the productionof bioabsorbable oligomers and isocyanate endcapping are within thepurview of those skilled in the art.

For example, the bioabsorbable oligomer can be prepared by dryingpurified monomer(s) used to form the bioabsorbable oligomer and thenpolymerizing at temperatures ranging from about 20° C. to about 220° C.,preferably above 75° C., in the presence of an organometallic catalystsuch as stannous octoate, stannous chloride, diethyl zinc or zirconiumacetylacetonate. The polymerization time may range from 1 to 100 hoursor longer depending on the other polymerization parameters but generallypolymerization times of about 12 to about 48 hours are employed. Inaddition, an initiator such as, for example, diethylene glycol, isemployed. Generally, the amount of initiator used will range from about0.01 to about 30 percent by weight based on the weight of the monomer.Preferably, the initiator will be present in the reaction mixture in anamount from about 0.5 to about 20 weight percent based on the weight ofthe monomer.

Once the bioabsorbable oligomer is formed, isocyanate endcapping can beachieved by reacting the oligomer with a diisocyanate. Suitablediisocyanates include hexamethylene diisocyanate, diisocyanatolysineethyl ester and butane diisocyanate. The conditions under which theoligomer is reacted with the diisocyanate may vary widely depending onthe specific oligomer being endcapped, the specific diisocyanate beingemployed, and the desired degree of end capping to be achieved.Normally, the polymer is dissolved in a solvent and added dropwise to asolution of the diisocyanate at room temperature with stirring. Theamount of diisocyanate employed can range from about 2 to about 8 molesof diisocyanate per mole of oligomer. Suitable reaction times andtemperatures range from about 15 minutes to 72 hours or more attemperatures ranging from about 0° C. to 250° C.

As another example, bioabsorbable isocyanate compounds can be preparedby reacting a multifunctional (e.g., polyhydric) initiator with a molarexcess of diacid to provide a diacid. This will add the bioabsorbablegroup to the initiator and provide free acid groups. Suitable diacidswhich will provide an absorbable linkage will be apparent to thoseskilled in the art and include succinic acid, adipic acid, malonic acid,glutaric acid, sebacic acid, diglycolic acid and the like. While theexact reaction conditions will depend upon the specific startingcomponents, generally speaking the initiator and the diacid are reactedat temperatures in the range of 25° C. to 150° C., for a period of timefrom 30 minutes to 24 hours at atmospheric pressure in the presence of atransesterification catalyst such as, for example stannous octoate,stannous chloride, diethyl zinc or zirconium acetylacetonate.

Once a diacid is formed, conversion thereof to an isocyanate can beaccomplished by techniques within the purview of those skilled in theart. For example, the free acid groups can be reacted with thionylchloride to produce the corresponding acylchloride followed by reactionwith sodium azide and heat to provide isocyanate groups.

Upon crosslinking, the present bioabsorbable compositions can be used astwo component adhesives or sealants. Cross-linking is normally performedby combining the two components of the composition optionally in thepresence of water and a catalyst, such as tertiary amine catalyst.

While not wishing to be bound by any theory, it is believed that theamine component of the composition reacts with the isocyanate componentof the composition to form polyurea thereby forming a crosslinkedpolyalkylene oxide polymer.

The exact reaction conditions for achieving cross-linking will varydepending on a number of factors such as the particular componentspresent in the bioabsorbable composition employed, the relative amountsof the components present in the bioabsorbable composition, the specificisocyanate present in the composition and the desired degree ofcross-linking. Normally, the cross-linking reaction is conducted attemperatures ranging from 20° C. to about 40° C. for thirty seconds toabout one hour or more. The amount of water employed will normally rangefrom about 0 moles to 1 mole per mole of isocyanate compound in thecomposition. While water is a preferred reactant to effect cross-linkingit should be understood that other compounds could also be employedeither together with or instead of water. Such compounds includediethylene glycol, polyethylene glycol and diamines, such as, forexample, diethylamino propanediol. Suitable catalysts for use in thecross-linking reaction include 1,4 diazobicyclo [2.2.2]octane,triethylamine, and diethylaminoethanol.

The amount of catalyst employed can range from about 0.005 grams toabout 5.0 grams per kilogram of the composition being cross-linked.

When the bioabsorbable composition is intended for implantationcross-linking may optionally be effectuated in situ using the waternaturally present in a mammalian body or with added water. However, tomore precisely control the conditions and extent of cross-linking, itmay be advantageous to partially cross-link the composition prior to itsuse as an implant.

The bioabsorbable compositions described herein can also be cross-linkedby the application of heat alone, or by exposure to diamine vapor. Thesecross-linking techniques are particularly useful when the compositionsare to be used as a coating, rather than as an adhesive or sealant.

In yet another embodiment a composition useful as a tissue adhesive orsealant includes a polyalkylenelene oxide having one or more isocyanatesubstituents combined with a bioabsorbable diamine compound.

The isocyanate-substituted polyalkylene oxide can be derived from anyC₂-C₆ alkylene oxide and can be homopolymeric or copolymeric. Thus, forexample, the isocyanate-substituted polyalkylene oxide can be derivedfrom ethylene oxide and be an isocyanate-substituted polyethylene oxide(PEO). As another example, the polyalkylene oxide can be derived frompropylene oxide and be an isocyanate-substituted polypropylene oxide(PPO). As yet another example, a combination of ethylene oxide andpropylene oxide can be used to form a random or block copolymer as theisocyanate-substituted polyalkylene oxide. The molecular weight of theisocyanate-substituted polyalkylene oxide should be selected to providedesired physical characteristics to the final composition. The molecularweight of the polyalkylene oxide backbone should be selected to providedesired physical characteristics to the final compound. Preferredbackbones have molecular weights in the range of 500 to 20,000,preferably 1000 to 10,000, most preferably 2000 to 3500.

In particularly useful embodiments, the polyalkylene oxide backbone hasa branched or multi-arm structure. For example, the polyalkylene oxidebackbone can be the result of polymerizing alkylene oxide monomer in thepresence of a multi-functional (e.g., polyhydric) initiator. Reactionconditions for producing branched or multi-arm polyalkylene oxidebackbones are known to those skilled in the art.

In one embodiment the isocyanate-substituted polyalkylene oxide compoundcorresponds to following formula (VIII):R′_(4-n)—C—(R)_(n)  (VIII)wherein the R′ groups can be the same or different at each occurrenceand are each individually selected from the group consisting of —H andC₁ to C₈ alkylene groups and the R groups can be the same or differentat each occurrence and are each individually selected from the groupconsisting of polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group, with the proviso that atleast two of the R groups are polyalkylene oxide groups substituted withat least one isocyanate group, and n is a number of from 2 to 4.

In another embodiment, the isocyanate-substituted polyalkylene oxidecompound corresponds to the following formula (IX):

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group, with the proviso that atleast two of the R groups are polyalkylene oxide groups substituted withat least one isocyanate group, and n is 2 to 6.

The isocyanate groups in the compounds of formula (VIII) and formula(IX) can be terminally located on the polyalkylene oxide arms, or,alternatively, substitution of the isocyanate groups can be at one ormore location along the polyalkylene oxide arms. Likewise, although asingle isocyanate group per polyalkylene oxide arm is preferred, it isalso contemplated that more than one and up to ten or more isocyanategroups per polyalkylene oxide arm may be present.

The number of isocyanate groups present on the polyalkylene oxidebackbone is selected to provide desired physical characteristics to thecompound upon exposure to moisture and/or to a diamine. A greater degreeof substitution will provide greater cross-linking which will provide amaterial that exhibits less swelling and less compliance. A lower degreeof substitution will yield a less cross-linked material having greatercompliance.

The preparation of isocyanate-substituted polyalkylene oxides is withinthe purview of those skilled in the art. In fact, suitableisocyanate-substituted polyalkylene oxides are commercially availablefrom Shearwater Polymers, Inc., Huntsville, Ala. Preferably, theisocyanate-substituted polyalkylene oxide is a diisocyanate.

The isocyanate-substituted polyalkylene oxide is combined with abioabsorbable amine, preferably a bioabsorbable diamine.

In one particularly useful embodiment, the bioabsorbable amine that iscombined with the isocyanate-substituted polyalkylene oxide is acompound of the following formula (X):NH₂—(CH₂)_(w)—(B)_(y)—(CH₂)_(w)—NH₂  (X)wherein B is a bioabsorbable group and w is 2 to 6 and y is 1 to 20.Bioabsorbable groups (B) include, for example, groups derived from anymonomer known to form a bioabsorbable polymer (including but not limitedto glycolic acid, glycolide, lactic acid, lactide, 1,4-dioxane-2-one,1,3-dioxane-2-one, ε-caprolactone and the like) or groups derived from adiacid which will provide an absorbable linkage (including but notlimited to succinic acid, adipic acid, malonic acid, glutaric acid,sebacic acid, diglycolic acid and the like).

Bioabsorbable amine compounds can be prepared by blocking the aminegroup on an alcohol amine and reacting the blocked alcohol amine with adiacid. This will add the bioabsorbable group to the alcohol amine andprovide free amine groups.

Suitable diacids which will provide an absorbable linkage will beapparent to those skilled in the art and include succinic acid, adipicacid, malonic acid, glutaric acid, sebacic acid, diglycolic acid and thelike. Suitable alcohol amines include, but are not limited to, C₁-C₆alcohol amines such as, for example, ethanolamine and propanolamine.

Blocking of the amine group of the alcohol amine can be achieved usingtechniques well known to those skilled in the art. For example, thealcohol amine can be reacted with benzylchloroformate to block the aminegroup so that reaction takes place between the diacid and the hydroxylgroup of the alcohol amine.

While the exact reaction conditions will depend upon the specificstarting components, generally speaking the blocked alcohol amine andthe diacid are reacted at temperatures in the range of 20° C. to 200°C., for a period of time from 30 minutes to 24 hours at atmosphericpressure in a suitable solvent such as, for example, THF. The resultingcompound is reduced with hydrogen and a palladium catalyst which resultsin decarboxylation and provides a diamine.

Upon crosslinking, the present bioabsorbable compositions can be used astwo component adhesives or sealants. Cross-linking is normally performedby combining the two components of the composition optionally in thepresence of water and a catalyst, such as tertiary amine catalyst.

While not wishing to be bound by any theory, it is believed that theamine component of the composition reacts with the isocyanate componentof the composition to form polyurea thereby forming a crosslinkedpolyalkylene oxide polymer.

The exact reaction conditions for achieving cross-linking will varydepending on a number of factors such as the particular componentspresent in the bioabsorbable composition employed, the relative amountsof the components present in the bioabsorbable composition, the specificisocyanate present in the composition and the desired degree ofcross-linking. Normally, the cross-linking reaction is conducted attemperatures ranging from 20° C. to about 40° C. for thirty seconds toabout one hour or more. The amount of water employed will normally rangefrom about 0 moles to 1 mole per mole of isocyanate compound in thecomposition. While water is a preferred reactant to effect cross-linkingit should be understood that other compounds could also be employedeither together with or instead of water. Such compounds includediethylene glycol, polyethylene glycol and diamines, such as, forexample, diethylamino propanediol. Suitable catalysts for use in thecross-linking reaction include 1,4 diazobicyclo [2.2.2]octane,triethylamine, and diethylaminoethanol.

The amount of catalyst employed can range from about 0.005 grams toabout 5.0 grams per kilogram of the composition being cross-linked.

When the bioabsorbable composition is intended for implantationcross-linking can optionally be effectuated in situ using the waternaturally present in a mammalian body or with added water. However, tomore precisely control the conditions and extent of cross-linking, itmay be advantageous to partially cross-link the composition prior to itsuse as an implant.

The bioabsorbable compositions described herein can also be cross-linkedby the application of heat alone, or by exposure to diamine vapor. Thesecross-linking techniques are particularly useful when the compositionsare to be used as a coating, rather than as an adhesive or sealant.

In another embodiment, the isocyanate polymer composition can bechemically altered to provide a desired charge on the polymer. Thepresence of charged groups on the polymer can enhance wound healing ineither hard or soft tissue. To impart a positive charge, a positivecharge inducing reactant such as, for example, diethylethanolamine, canbe introduced into the polymer. To impart a negative charge, the polymermay be reacted with a negative charge inducing reactant such as, forexample, carboxymethanol.

The bioabsorbable compounds and compositions described herein areadvantageously useful as a surgical adhesive or sealant, for example,for joining portions of body tissue together, or for adhering a surgicaldevice such as a surgical mesh, fastener, implant, etc., to soft bodytissue.

Upon contact with water, the bioabsorbable isocyanate polymercomposition undergoes cross-linking and the isocyanate groups areconverted to urea or urethane moieties, which promotes adhesion to hardand/or soft body tissue.

It will be understood that various modifications may be made to theembodiments disclosed herein. For example, the compositions inaccordance with this disclosure can be blended with other biocompatible,bioabsorbable or non-bioabsorbable materials. Therefore, the abovedescription should not be construed as limiting, but merely asexemplifications of preferred embodiments. Those skilled in art willenvision other modifications within the scope and spirit of the claimsappended hereto.

1. A method comprising: contacting tissue with a bioabsorbable compoundcomprising an amine-substituted polyalkylene glycol and a bioabsorbableisocyanate of the formula:R′_(4-n)—C—(R)_(n) wherein the R′ groups can be the same or different ateach occurrence and are each individually selected from the groupconsisting of —H and C₁ to C₈ alkylene groups, n is a number of from 2to 4, and the R groups can be the same or different at each occurrenceand are each individually selected from the group consisting ofpolyalkylene oxide groups and polyalkylene oxide groups substituted withat least one isocyanate group having the formula:—[A]_(n)—NCO wherein A is a bioabsorbable group and n is from 1 to about20, with the proviso that at least two of the R groups are polyalkyleneoxide groups substituted with at least one isocyanate group; and joiningthe tissue with other tissue to close a wound.
 2. A method as in claim1, wherein the amine substituted polyalkylene glycol has the formula:R′_(4-n)—C—(R)_(n) wherein the R′ groups can be the same or different ateach occurrence and are each individually selected from the groupconsisting of —H and C₁ to C₈ alkylene groups and the R groups can bethe same or different at each occurrence and are each individuallyselected from the group consisting of polyalkylene oxide groups andpolyalkylene oxide groups substituted with at least one amine group,with the proviso that at least two of the R groups are polyalkyleneoxide groups substituted with at least one amine group, and n is anumber of from 2 to
 4. 3. A method as in claim 1, wherein theamine-substituted polyalkylene glycol has the formula:

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one amine group, with the proviso that atleast two of the R groups are polyalkylene oxide groups substituted withat least one amine group, and n is 2 to
 6. 4. A method comprising:contacting tissue with a bioabsorbable composition comprising anamine-substituted polyalkylene glycol and a bioabsorbable isocyanate ofthe formula:

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one isocyanate group having the formula:—[A]_(n)—NCO wherein A is a bioabsorbable group and n is from 1 to about20, with the proviso that at least two of the R groups are polyalkyleneoxide groups substituted with at least one isocyanate group, and n is 2to 6; and joining the tissue with other tissue together to close awound.
 5. A method as in claim 4, wherein the amine substitutedpolyalkylene glycol has the formula:R′_(4-n)—C—(R)_(n) wherein the R′ groups can be the same or different ateach occurrence and are each individually selected from the groupconsisting of —H and C₁ to C₈ alkylene groups and the R groups can bethe same or different at each occurrence and are each individuallyselected from the group consisting of polyalkylene oxide groups andpolyalkylene oxide groups substituted with at least one amine group,with the proviso that at least two of the R groups are polyalkyleneoxide groups substituted with at least one amine group, and n is anumber of from 2 to
 4. 6. A method as in claim 4, wherein theamine-substituted polyalkylene glycol has the formula

wherein the R groups are the same or different at each occurrence andare each individually selected from the group consisting of —H, C₁ to C₈alkylene groups, polyalkylene oxide groups and polyalkylene oxide groupssubstituted with at least one amine group, with the proviso that atleast two of the R groups are polyalkylene oxide groups substituted withat least one amine group, and n is 2 to 6.